End-stage renal disease (ESRD) is a chronic condition that affects approximately 700,000 persons each year (worldwide), at an estimated cost exceeding $20 billion. It is generally agreed that once chronic renal insufficiency is established, renal disease is almost always progressive. The clinical course of most renal disease can be separated into the etiologic or initiation stage, which is followed by the progression of pathogenetic stage. Although the causes vary widely, recent studies indicate that the progression component that culminates in ESRD shares many features in common among diverse renal disorders. The unifying theme of this Program Project is the exploration of molecular mechanisms underlying the progression of diseases of different etiologies to a common outcome, end-stage renal failure. Three renal disease with clear-cut etiologies (Alport syndrome, autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy) were selected to pursue the overall research objectives. The Program Project is composed of four scientific projects that address specific elements of disease progression, and a supportive administrative core. Project 1 will test the hypothesis that the progression to ESRD in X-linked Alport syndrome evolves from a congenital malformation of the glomerular basement membrane (GBM) which involves COL4A5 gene mutations that arrest a developmental switch from an immature alpha1(IV)/alpha2(IV) collagen network to a mature alpha3(IV)/alpha4(IV)/alpha5(IV) network, and the persistence of this immature network predisposes the GBM to proteolytic degradation. Project 2 will test the hypothesis that the functions of polycystin-1 and polycystin-2, which are mutated in ADPKD, are mediated by signal transduction, and as such, that these proteins are substrates for phosphorylation, and that phosphorylation of these proteins affects their interactions with each other and with other signal transduction proteins, in particular Galpha subunits of heterotrimeric G-proteins. Project 3 will test the hypothesis that cyst activating factor, a novel neutral lipid that accumulates in cysts of ADPKD patients, promotes fluid secretion and cellular proliferation by cyst epithelial cells, and induces chemokine, cytokine and metalloproteinase production in renal epithelial cells and macrophages. The long term goal is for the research to contribute to novel treatments to slow or arrest the progression of these renal disorders.